1、Why are Biomarkers Important Prostate Cancer diagnosed in 200,000 men annually in the united states 30,000 cancer specific deaths per year Yet,a substantial portion of cancers diagnosed through PSA screening do not progress to clinically significant disease.Problem with PSA screening It is not speci
2、fic,resulting in a negative biopsy rate of up to 70%in some series European randomized trial:1410 men screened and 48 treated to prevent 1 death from prostate cancer Sweedish Randomized trial of watchful waiting:Relative risk for surgery:0.62(0.44-0.87)NNT 15 overall and 7 for men younger than 65yHo
3、w do we improve screening and treatment decisions?Clinical nomograms Include Gleason Score,positive cores,percent involvement of cores,and PSA Other risk factors:family history,age,race Biomarkers Supplement known clinical informationClinical Nomogram:Kattan NomogramStephenson et al,J natl CI,2006 H
4、ow can biomarkers improve management?Categories of biomarkersUrine BasedBlood BasedTissu BasedUrine Based Biomarkers Proteins Urinary/serum psa ratio Annexin A3 MMP9 Proteomics DNA Glutathione-S-transferase P1 Other methylation-specific PCR assays RNA PCA3 TMPRSS2-ERG gene fusionRoobol et al,Acta on
5、cologica,2011Urinary PCA3 Developed from differential expression of noncoding RNAs in prostate cancer versus other prostate conditions Commercially available,approved diagnostic test Collected from urine sample following a firm DRE Could function as a first line screen or prognostic indicatorUrinary
6、 PCA3:First line screen Several studies show superior overall specificity to PSA:80-90%,but include only patients with elevated PSA In the REDUCE trial the placebo test characteristics for PSA were:Se=0.518 Sp=0.629 PCA3 in patients with PSA 4-10ng/ml:Specificity:71-93%Sensitivity:53-84%Is PCA3 Bett
7、er than PSA for CaP diagnosis?ERSPC:prostate biopsy trigger:PSA 3 or PCA3 10 In 721 biopsied,PCA3 performed only marginally better:AUC:PCA3=0.64 PSA=0.58Roobol et al,Eur Urol,2010PCA3 and TMPRSS2-ERG fusion Fusion of a strong androgen promoter(transmembrane serine protease)and an oncogene Further im
8、proved diagnostic accuracy(AUC)PCA3:0.65 PCA3+Fusion:0.77 PCA3+gene-fusion+PSA:0.80Aubin et al,J Urol,2008PCA3:prognostic indicator Conflicting studies show a positive relationship1 with cancer aggressiveness or no relationship2 Reduce Trial-chemoprevention of CaP with Dutasteride3:Weak association
9、of PCA3 with Gl 7 or higher cancer OR:1.017(CI95%:1.01-1.03)Though low numbers of high grade prostate cancer weakens the analysis1.Hessels et al,Prostate,2010 2.Whitman et al,J Urol,2008 3.Aubin et al,Urology,2011Blood Based biomarkers Diagnosis PSA PSA velocity Free PSA Pro-PSA BPH-associated PSA P
10、rognosis Human Kallikrein 2 Urokinase plasminogen activator Transforming Growth factor 1 Interleukin-6 EndoglinLimitations of Total PSA Neoplastic cells produce varying levels of PSA Biologic variation:Oscillations of PSA up to 30%in range of 0.1-20ng/ml Different Assays(WHO standard)Sensitivity:52%
11、Specificity:63%What Cut-off?PSA(ng/ml)Percent CaP (%)0.66.60.6-1.010.11.1-2.017.02.1-3.023.93.1-4.026.9PCPTThompson et al,NEJM,2004PSA:Long-term risk Malmo Preventative Medicine Study 462 CaP median f/u 18y matched to 1,222 controls Total PSA at age 44-50 was comparedTotal PSA at age 44-50y (ng/ml)O
12、dds Ratio of CaP 0.501.000.51-1.02.511.01-2.07.022.01-3.019.01Ulmert et al,BMC Med,2008PSA Velocity Measurement of change in total PSA over time Two large prospective trials found no independent predictive value beyond total PSA and other standard variables(PCPT and ERSPC)1.Shariat et al,Acta Onc,20
13、11 2.Damico et al,NEJM,2004 3.Carter et al,J NCI,2006Diagnosis Increase risk of death determined at PSAv levels greater than 0.35 2.0 ng/ml per year May not predict early progression but an indication of aggressive disease beyond treatment windowPrognosisPercent Free PSA Isoform of PSA that remains
14、unbound in plasma Percent free PSA relative to the total PSA is FDA approved as an adjunct to total PSA between 4-10ng/ml fPSA 25%used as a trigger for biopsy Multicenter,prospective trial Specificity:95%,Sensitivity:20%over PSA AUC:%fPSA=0.72PSA:0.53 When use 10-12 core biopsy:efficiency decreasesC
15、atalona et al,JAMA,1998Canto et al,J Urol,2004Combined panel of PSA isoforms ERSPC:For every 1,000 unscreened men,the model,if used to determine biopsy:Reduce biopsy rates by 573 Miss 31/152 low grade CaP 3/40 high grade CaPVickers et al,BMC Med,2008 Endoglin:CD 105,a cell surface co-receptor for TG
16、F1 and 3 Found on immature blood vessels:Angiogenesis Pre-prostatectomy levels may predict higher gleason score and PSA recurrenceSvatek et al,CCR 2008Combining Panel of Markers and Nomogram Biomarkers used to supplement not replace clinical data to improve accuracy of prognosis Kattan nomogram+biom
17、arker panel:TGF-1,IL-6R,IL-6,endoglin,VEGF,VCAM-1 Predictive accuracy of the Kattan nomogram improved by 15%71.6%versus 86.6%Shariat et al,Acta Onc,2011Tissue Based Biomarkers Diagnostic High molecular weight cytokeratin p63 AMACR Prognostic Human kallikrein type 2 Prostate specific membrane antigen
18、 Ki-67 Androgen receptor Gene fusions PTEN P53 SPINK1/TATI MSMB EZH2 Heat shock proteins DNA methylation HER2Prostate Specific Membrane Antigen Transmembrane glycoprotein negatively regulated by androgens and overexpressed in androgen independent CaPIncreased expression associated with higher grade
19、and biochemical recurrencePerner S,et al,Human Path,2007Translating biomarkers into therapeutic Targets PSMA PSMA-antibody drug conjugate currently in phase 1 trial Castration-resistent metastatic CaP Endoglin TRC105 is a human/murine chimeric monoclonal antibody that binds to endoglin,thus inhibiti
20、ng angiogenesis Phase 1/phase 2 trial for CRPCnih.gov,2011Summary Biomarkers serve as a powerful adjunct to the diagnosis and management of prostate cancer Biomarkers are testable in the urine,blood,and prostate cancer tissue Further validation of these biomarkers and research into potential therapeutic targets is needed
